New Flexible Analogues of 8-Aza-7-deazapurine Nucleosides as Potential Antibacterial Agents

Abstract

A variety of ribo-, 2'-deoxyribo-, and 5'-norcarbocyclic derivatives of the 8-aza-7-deazahypoxanthine fleximer scaffolds were designed, synthesized, and screened for antibacterial activity. Both chemical and chemoenzymatic methods of synthesis for the 8-aza-7-deazainosine fleximers were compared. In the case of the 8-aza-7-deazahypoxanthine fleximer, the transglycosylation reaction proceeded with the formation of side products. In the case of the protected fleximer base, 1-(4-benzyloxypyrimidin-5-yl)pyrazole, the reaction proceeded selectively with formation of only one product. However, both synthetic routes to realize the fleximer ribonucleoside (3) worked with equal efficiency. The new compounds, as well as some 8-aza-7-deazapurine nucleosides synthesized previously, were studied against Gram-positive and Gram-negative bacteria and M. tuberculosis. It was shown that 1-(β-D-ribofuranosyl)-4-(2-aminopyridin-3-yl)pyrazole (19) and 1-(2',3',4'-trihydroxycyclopent-1'-yl)-4-(pyrimidin-4(3H)-on-5-yl)pyrazole (9) were able to inhibit the growth of M. smegmatis mc2 155 by 99% at concentrations (MIC₉₉) of 50 and 13 µg/mL, respectively. Antimycobacterial activities were revealed for 4-(4-aminopyridin-3-yl)-1H-pyrazol (10) and 1-(4'-hydroxy-2'-cyclopenten-1'-yl)-4-(4-benzyloxypyrimidin-5-yl)pyrazole (6). At concentrations (MIC₉₉) of 40 and 20 µg/mL, respectively, the compounds resulted in 99% inhibition of M. tuberculosis growth.

Keywords: antibacterial activity; antituberculosis activity; fleximer; inhibitor; nucleoside analogues.

Scheme 1

Synthesis of fleximer analogues. A—chemo-enzymatic synthesis: PNP and UP E. coli uridine or 2′-deoxyuridine; B—chemical synthesis: (i) HMDS, Py, (NH₄)₂SO₄; (ii) Ac₄Rib, TMSOTf; (iii) 7N NH₃/MeOH, 36 °C; a: Pd/C, H₂, MeOH, TFA; b: H₂, Pd/C, EtOH.

Scheme 2

Synthesis of fleximer analogues of 5′-norcarbocyclic nucleosides: (a) 6-oxobicyclo [3.1.0.]hex-2-ene, Pd(PPh₃)₄, DMF/THF; (b) OsO₄, Dioxane/H₂O; (c) Pd/C, H₂, MeOH.

Figure 1

8-Aza-7-deazapurine fleximer nucleoside analogues.